ABSTRACT Cancer survivors across most primary tumor types are at a heightened risk for secondary myeloid neoplasms (tMN), a highly lethal disease. However, the mechanism underlying this association and the patient populations at adequately high risk to warrant intervention are not well-established. Clonal hematopoiesis (CH) is a pre- leukemic state that confers a substantially increased risk of tMN. We have developed a database of 17,500 patients who have undergone targeted blood sequencing with associated comprehensive clinical annotation. Preliminary data from this cohort shows that exposure to specific oncologic therapies is associated with CH. We show that subsets of patients at high risk of tMN can be defined based on CH mutational and clinical characteristics. Our central hypothesis is that CH can be used to predict tMN risk and that this ?high-risk? CH is promoted by exposure to specific oncologic therapies. First, we propose to characterize how prior exposure specific oncologic therapies is related to the presence of CH and clonal expansion. We will study this in 25,000 solid tumor patients who were tested for CH through routine clinical molecular profiling workup. We will compare CH mutational characteristics among previously treated (60%) and untreated (40%) solid tumor patients. Second, we will define the molecular and clinical features associated with myeloid neoplasm in solid tumor patients. This will be achieved though sequencing of tMN cases and matched controls selected from bio-banked blood samples of solid tumor patients. We hypothesize that consideration of CH molecular features in combination with clinical factors and treatment exposures predict development of myeloid neoplasm development in cancer patients. This will result in the development of a risk-prediction model for t-MN development in solid tumor patients. Third, we will define the timing of CH mutation acquisition in patients receiving high-risk therapy through serial mutational profiling. We hypothesize that exposure to high-risk therapy drives clonal expansion of pre-existing CH clones present in low levels in pre-treatment blood samples. To achieve this, prospective collection of pre-treatment, mid-treatment and post-treatment blood samples will be undertaken. Our research proposal is designed to deliver a statistically powered and evidence-based resource that will enable a detail understanding of the relationships between CH, treatment exposures and subsequent risk of tMN. Our findings will enable the development of genomic based risk assessment of tMN in solid tumor patients. This will guide rational treatment decisions for solid tumor patients across a variety of primary sites aimed at minimization of tMN risk, a major barrier to long-term survival.